Production of 5 (4-aminobutyl)-hydantoin and of intermediates therefor



United States Patent O F 3,078,274 PRODUCTION OF'5(4-AMINOBUTYL)-HYDANTOIN AND OF INTERMEDIATES THEREFOR Arthur 0.Rogers, Lewiston, N.Y., assigrion to E.', I; du Pont de Nemours and;Company, Wilmington,; Deh, a corporation of Delaware; No Drawing. FiledJune 4, 1959, Ser. No. 813,002 9 Claims. (U. 260-,.-309.5)

This invention relates toS -halovaleraldehyde semicarbazones, theirpreparation and use in preparing -(4- aminobutyl)-hydantoin which isavaluablelysine intermediate.

It is anobject of the inventionto provide amethod for preparingS-chloroand S-bromovaleraldehyde semicar bazone s, which are newcompounds. Avfurtherobject is a method of converting said semicarbazonesto 5-(4 aminobutyl)-hydantoin. Still further objects will be apparentfrom the following description.

The objects, of the invention are accomplished by the provision ofS-chloroor 5 -bromovaleraldehyde semicarbazone and by the production ofsaid semicarbazone by the hydrogenation of S-chlorovaleronitrile orS-bromovaleronitrile with hydrogen in the. presence of a hydrogenationcatalyst and semicarbazide. In a further embodiment of the invention,the S-chloroor 5-bromovaleraldehyde semicarbazone intermediate isreacted with cyanide ions, ammonium ions and carbonate ions in an inertpolar liquid solvent to obtain the valuable lysine. intermediate, 5-(4-aminobutyl) -hyd antoin.

The reaction for converting S-chlorovaleronitrile to 5-chlorovaleraldehyde semicarbazone can be represented as follows:

C1 01 I JH HzNNHCO-NE2 ,+7H (0119.4 NH:

I TNHOO-NH2 5-chlorovaleronitrile 5-chlorovaleraldehyde semicarbazone 5-(t-aminobutyl) hydantoin Semiearbazide S-bromovaleraldehydesemicarbazone can be converted to 5-(4-aminobutyl)-hydantoin by asimilar reaction.

3,078,274 Patented Feb, 19, 1053 The production of the halovaleraldehydesemicarbazone as illustrated by reaction (1) canbe carriedout at-item'-peraturesrangingtrom about-.30 to.200 C. and hydro"- gen pressures ofabout 0:1 to 1000. atmospheres. Temperatures of -10 tolOO. C. andhydrogenpressures of lit-o 400 atmospheresare preferred. Thepreferredihydro genation catalystis porousnickel, such as the-well-knownalloy-skeleton nickel. catalyst. commonly referred to as Raneynickel.However, any other hydrogenation catalyst which is active at the abovetemperatures can-.b,e used. Examples of these are platinum, palladiumandcobalt.

Hydrogenationreaction (l) is preferably, carried out employing thehalovaleronitrile in the fornrofa solution or suspensionin aninertliquidvdiluent such aswater or a saturated". aliphatic alcoholcontaining 1 to-4 carbon atoms, or a mixture ,of-such diluents.Preferred diluents are methanol, ethanol, and aqueous methanol orethanol containing up-to 60% water by volume; The, concentration of thehalovaleronitrile in the mixture to be hydrogenatedmay be variedconsiderably but generally will range from about lto 50%, the preferredconcen trations being 5 to 30% by weight of the mixture.

It isv essential'that semicarbazidebe present during the hydrogenation.Itmay be supplied asthefreeb'ase, or as a mixture of a salt thereof(e.g.-, the hydrochloride) with an acid acceptor such as an alkali metalacetate, carbonate or hydroxide. Approximtely l,mole of'semicarbazide,will generally be used per mole of the halovaleronitrile. Smallerproportions, e.g., down to 0.5 mole of the semicarbazide per mole of thehalovaleronitrile, can be used but are not preferred becauseofthe'resulting sacrifice in product yield. Larger proportions, e.g., upto 2 moles or more per mole of the halovaleronitrile can be'usedbutresult in no added advantages.

The halovaleraldehy-de semicarbazone product of reaction (1) can berecovered conveniently from the reaction mixture by conventionalcrystallization methods. Thus, the mixture, after separating thecatalyst, can be concentrated by vacuum evaporation on the steam bathand then allowed to cooltto crystallize out the semicarbazone product.

Specific nitriles have previously been hydrogenated in the presence ofsemicarbazide to obtain the correspondingaldehyde semicarbazones (seePlieninger and Werst, Angewandte Chcmie, 67, 156 (1955)). However, sofar as I am aware such a method has not previously been employed toconvert any chloroor bromonitrile tothe corresponding aldehydesemicarbazone. This is not surprising since a chlorine or bromine atom,particularly in a terminal position as in the presenthalovaleronitriles, would have-been expected to be removed during thehydrogenation and to result in rapid poisoning of the. hydrogenationcatalyst. My discovery that the present halovaleronitriles could besuccessfully converted to the corresponding halovaleraldehydesemicarbazone was entirely unexpected.

The conversion of the halovaleraldehyde semicarba-zone to5-(4-aminobutyl)-hydantoin by reaction with cyanide, ammonium andcarbonate ions can be carried out under .essentially those conditionswhich are generally known to be suitable for converting aldehydes orketones to corresponding hydantoins by reaction with cyanide, ammoniumand carbonate ions. The reaction should be carried out in an inert polarsolvent, preferably water or a lower alcohol or a mixture of suchsolvents, Hydrogen. cyanide,-amm onia and carbon dioxide, are convenientsources of the reactant ions, as indicated in reaction (2). Othermaterials, such as the alkali metal cyanides and carbonates, ammoniumhydroxide and ammonium salts such as ammonium carbonate, can obviouslybe added to the reaction mixture to provide one or more of the reactantions.

Suitable temperatures for carrying out the reaction to form-(4-aminobutyl)-hydantoin range from about 40 to 220 C. Operation underpressure will, of course, be required at the higher temperaturesindicated. The preferred temperatures range from 60 to 150 C. Thereaction is completed in about 3 to 4 hrs. at 100 C. and in shortertimes at higher temperatures. A substantial excess of any of thereactants can be used but an excess of the semicarbazone will generallybe avoided for reasons of economy. Generally suitable proportions are 1to 1.5 moles of cyanide ions, 1 to moles of carbonate ions and 3 to 40or more moles of ammonium ions per mole of the semicarbazone. Aconsiderable excess of ammonium ions, e.g., at least 10 moles per moleof the semicarbazone, is preferred to favor formation of the desiredprimary amine group in the product.

As indicated by Equation 2, semicarbazide is liberated as a by-productof the hydantoin-forming reaction. It will generally be desirable forreasons of economy to recover such by-product. This may be effected inconventional ways, e.g., by crystallization or ion-exchange methods.Similar methods may be used to isolate the 5-(4-aminobuty1)-hydantoinproduct from the reaction mixture. However, isolation at this stage isnot essential if the aminobutyl hydantoin is to be used as anintermediate for producing some other product, since the crudeaminohydantoin is quite suitable for direct use in further processing,e.g., hydrolysis to lysine.

It has previously been proposed to react certain aldehyde semicarbazoneswith hydrogen cyanide and ammonium carbonate to obtain hydantoinscorresponding to the aldehydes of the semicarbazones used, e.g.,S-(npropyl)-hydantoin from n-butyraldehyde semicarbazone. In contrast,the present hydantoin-forming reaction yields 5-(4-aminobutyl)-hydantoininstead of 5-(4-hal0- butyl)-hydantoin which would have been expected tobe obtained from the starting halovaleraldehyde semicarba-zone. In otherWords, the present hydantoin-forming reaction involves the simultaneousformation of the hydantoin ring and the substitution of the terminalchlorine or bromine atom by an amino group which is highly desirable.

The invention is illustrated by the following examples.

Example 1 A glass-lined rocker reaction bomb was charged withS-chlorovaleronitrile (35 g., 0.3 mole), semicarbazide hydrochloride(33.5 g., 0.3 mole), sodium acetate trihydrate (54.5 g., 0.4 mole),Raney nickel (settled slurry in water, equivalent to about g. Ni) andaqueous ethanol (290 cc., 60% ethanol by volume). The bomb was purgedwith hydrogen, then pressured with hydrogen to a pressure of 1520p.s.i.g. The hydrogen pressure dropped 130 p.s.i. during 46 min. at roomtemperature, following which the bomb was re-pressured with hydrogen to1530 p.s.i.g. The pressure dropped an additional p.s.i. over the next 34min. and thereafter remained constant. The catalyst was filtered 01f andwashed with ethanol, then with water. The filtrate and washings wereevaporated on the steam bath under reduced pressure to about 150 cc. Theproduct S-chlorovaleraldehyde semicarbazone separated from the resultingmixture as a liquid layer which crystallized readily when cooled andrubbed. After standing overnight to complete crystallization, thecrystals were filtered off and dried in a. vacuum oven. Yield, 24.9 g.(46.7% based on nitrile charged), M.P. 9091.5 C. After recrystallizationfrom isopropanel, the product melted at 94-96 C. and analyzed: C,

I with an excess of pyridine.

4 41.03, 41.30%, H, 6.70, 7.00%; N, 23.61%. Calculated for C H N OCl: C,40.56%; H, 6.81%; N, 23.65%.

The use of S-bromovaleronitrile in place or" 5chlorovaleronitrile in themethod of Example 1 yields S-bromovaleraldehyde semicarbazone.

Example 2 A charge of S-chlorovaleraldehyde semicarbazone (6.0 g., 0.034mole), ammonium carbonate (11.0 g., 0.07 mole), ammonium hydroxide (55cc., 0.07 mole NH and hydrogen cyanide (1.6 cc., 0.04 mole) was heatedat C. in a sealed Carius tube for 4 hrs. The resulting solution wasevaporated to essentially constant weight on the steam bath underreduced pressure. The residue was shown by paper chromatography tocontain 5-(4- aminobuty1)-hydantoin (estimated yeild, 10% based upon thesemicarbazone charged). The above residue was transferred with a minimumamount of water to a Carius tube. After adding concentrated hydrochloricacid (25 cc.), the tube was sealed and heated for 16 hrs. at C. Theproduct solution was evaporated to dryness on the steam bath underreduced pressure. The resulting residue was extracted with 50 cc. of 95%ethanol, the undissolved material was filtered off and the filtratetreated There resulted a gummy precipitate which hardened on standing.This material was shown by paper chromatography and mixed melting pointto be mainly DL-lysine monohydrochloride.

The present invention provides a way of making 5- chloro and5-bromovaleraldehyde semicarbazones and a method for converting thesenew compounds to 5-(4- aminobutyl)-hydantoin which is a valuable lysineintermediate.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:

1. The method of producing a halovaleraldehyde semicarbazone comprisinghydrogenating a compound of the group consisting ofS-chlorovaleronitrile and S-bromovaleronitrile in the presence of ahydrogenation catalyst and semicarbazide, said catalyst being selectedfrom the group consisting of porous nickel, platinum, palladium andcobalt.

2. The method of producing a halovaleraldehyde semicarbazone comprisinghydrogenating a compound of the group consisting ofS-chlorovaleronitrile and 5-bromovaleronitrile in solution in an inertdiluent in the presence of a hydrogenation catalyst and of at least 1mole of semicarbazide per mole of said compound, said catalyst beingselected from the group consisting of porous nickel, platinum, palladiumand cobalt.

3. The method of claim 2 employing a porous nickel catalyst.

4. The method of claim 2 employing S-chlorovaleronitrile.

5. The method of claim 4 employing a porous nickel catalyst.

6. The method of producing 5-(4-aminobutyD-hydantoin comprisinghydrogenating a compound or the group consisting ofS-chlorovaleronitrile and S-bromovaleronitrile in the presence of ahydrogenation catalyst selected from the group consisting of porousnickel, platinum, palladium and cobalt and of semicarbazide to obtain aS-halovaleraldehyde semicarbazone and reacting said semicarbazone withcyanide ions, ammonium ions and carbonate ions in an inert polarsolvent.

7. The method of producing 5-(4-aminobnty1)-hydantoin comprisinghydrogenating 5-chlorovaleronitrile in the presence of a hydrogenationcatalyst selected from the group consisting of porous nickel, platinum,palladium and cobalt and of semicarbazide and reacting the resulting5-chlorovaleraldehyde semicarbazone with cyanide ions, ammonium ions andcarbonate ions in an inert polar solvent.

8. The method of claim 6 employing a porous nickel catalyst.

9. The method of c1aim 7 employing a porous nickel 2,937,184 Coker et211. L May 17, 1960 Catalyst FOREIGN PATENTS References Cited in thefile of this patent 700,825 Great Britain Dec. 9, 1953 UNITED STATESPATENTS 5 OTHER REFERENCES 2,564,649 Rogers Aug. 14, 1951 Kling: Chem.Abstracts, volume 3, page 1280 (1909).

2,889,332 Coker et a1 June 2, 1959 Hibbert et a1.: Chem. Abstracts,volume 17, page 1434 2,889,333 Coker et a1 Jun 2, 1959 (1923).

1. THE METHOD OF PRODUCING A HALOVALERADEHYDE SEMICARBAZONE COMPRISINGOF PRODUCING A COMPOUND OF THE GROUP CONSISTING OF 5-CHLOROVALERONITEAND 5-BROMOVALERONITRILE IN THE PRESENCE OF A HYDROGENATION CATALYST ANDSEMICARBAZIDE, SAID CATALYST BEING SELECTED FROM THE GROUP CONSISTING OFPOROUS NICKEL, PLATINUM, PALLADIUM AND COBALT.
 6. THE METHOD OFPRODUCING 5-(4-AMINOBUTYL)-HYDAR TION COMPRISING HYDROGENATING A CMPOUNDOF THE GROUP CONSISTING OF 5-CHLOROVALERONITRILE AND5-BROMOVALERONITRILE IN THE PRESENCE OF A HYDROGENATION CATALYSTSELECTED FROM THE GROUP CONSISTING OF POROUS NICKEL, PLATINU, PALLADIUMAND COBALT AND OF SEMICARBAZDE TO OBTAIN 5-HALOVALERALDEHYDESEMICARBAZONE AND REACTING SAID SEMICARBAZONW WITH CYANIDE IONS,AMMONIUM IONS AND CARBONATE IONS IN AN INERT POLAR SOLVENT.